Chagas disease affects 17 million people and a further 100 million people are at risk for infection with Trypanosoma cruzi, the parasitic cause of Chagas disease, throughout Latin America. Approximately 300,000 people develop Chagas disease each year resulting in an enormous health care burden. The prevalence of T. cruzi infection is growing in the U.S., and surveys of blood bank samples (from apparently healthy individuals) show prevalence rates ranging between 1 in 5000 and 1 in 9000. Approximately 40% of infected individuals will remain asymptomatic throughout their lives. However, about 60% of infected individuals will progress to chronic Chagas disease. The cardiac form of Chagas disease is highly debilitating, resulting in progressive cardiomyopathy. There is no vaccine for T. cruzi infection and available drugs are of questionable efficacy in reducing parasitemia after the initial acute phase of infection. There are no effective pharmaceutical treatments for Chagas disease. Unfortunately, the mechanisms underlying development of chronic Chagas disease remain poorly understood. We will assess ECG and immunological phenotypes correlated with Chagas disease in 1000 individuals who are infected with T. cruzi and who belong to large extended pedigrees. The goal of the project is to identify genetic determinants of progression to the cardiac form of Chagas disease in this sample. These individuals will be characterized for one million SNPs to facilitate genome-wide analyses designed to identify genes influencing disease progression. An additional 500 uninfected individuals from these same pedigrees will be employed to aid the identification of genetic variants that specifically are involved in genotype-by-infection interaction. The 10 most promising genes will then be resequenced to identify the functional variants responsible for the observed phenotypic variation in disease progression. Finally, a confirmation study of the best associated sequence variants will be performed in 500 unrelated infected cases with severe cardiac disease and 500 unrelated infected asymptomatic controls. Knowledge of the genes that are causally involved in determination of disease progression will significantly advance our knowledge of mechanisms underlying development of Chagas disease, suggest new pathways to be considered in potential drug development efforts, and allow matching of available pharmaceutical compounds to novel drug targets suggested by genetic analysis. PUBLIC HEALTH RELEVANCE: Chagas disease affects 17 million people and a further 100 million people are at risk for infection with Trypanosoma cruzi, the parasitic cause of Chagas disease, throughout Latin America. Approximately 300,000 people develop Chagas disease each year resulting in an enormous health care burden. There is no vaccine for T. cruzi infection and no effective for chronic Chagas disease. Knowledge of the genes that are causally involved in determination of disease progression will significantly advance our knowledge of mechanisms underlying development of Chagas disease, suggest new pathways to be considered in potential drug development efforts, and allow matching of available pharmaceutical compounds to novel drug targets suggested by genetic analysis.